ABSTRACT
Six-transmembrane epithelial antigen of the prostate-1 (STEAP-1) is a novel cell surface protein highly expressed in primary prostate cancer, with restricted expression in normal tissues. In this report, we show STEAP-1 expression in prostate metastases to lymph node and bone and in the majority of human lung and bladder carcinomas. We identify STEAP-1 function in mediating the transfer of small molecules between adjacent cells in culture, indicating its potential role in tumor cell intercellular communication. The successful generation of two monoclonal antibodies (mAb) that bind to cell surface STEAP-1 epitopes provided the tools to study STEAP-1 susceptibility to naked antibody therapy. Both mAbs inhibited STEAP-1-induced intercellular communication in a dose-dependent manner. Furthermore, both mAbs significantly inhibited tumor growth in mouse models using patient-derived LAPC-9 prostate cancer xenografts and established UM-UC-3 bladder tumors. These studies validate STEAP-1 as an attractive target for antibody therapy in multiple solid tumors and provide a putative mechanism for mAb-induced tumor growth inhibition.
Subject(s)
Antibodies, Monoclonal/pharmacology , Antigens, Neoplasm/drug effects , Cell Communication/drug effects , Oxidoreductases/drug effects , Prostatic Neoplasms/metabolism , Animals , Antigens, Neoplasm/metabolism , Blotting, Western , Bone Neoplasms/metabolism , Bone Neoplasms/secondary , Flow Cytometry , Humans , Immunohistochemistry , In Vitro Techniques , Lung Neoplasms/metabolism , Lung Neoplasms/secondary , Lymphatic Metastasis/pathology , Male , Mice , Neoplasm Transplantation , Oxidoreductases/metabolism , Prostatic Neoplasms/pathology , RNA, Small Interfering , Urinary Bladder Neoplasms/metabolism , Urinary Bladder Neoplasms/secondary , Xenograft Model Antitumor AssaysABSTRACT
BACKGROUND: It has recently been shown that treatment of animals with antibodies to CD154 (CD40L), allows for prolongation of cardiac allograft survival, but does not inhibit development of graft vasculopathy. CD8(+) T cells have been implicated in this effect. In this study we assess the role of CD40-CD154 interactions and CD40-independent CD8(+) T cells in the permanent and complete absence of CD40 by using donors and recipients genetically deficient in CD40. METHODS: Hearts from BALB/c CD40(-/-) donors were transplanted into C57BL/6 CD40(-/-) recipients in the presence or absence of CD8(+) T-cell depletion. At Day 60, hearts were examined for vasculopathy using quantitative morphometry and numbers of infiltrating T cells were counted. The intragraft expression of interferon-gamma (IFN-gamma), transforming growth factor-beta1 (TGF-beta1), interleukin-4 (IL-4), eotaxin and CCR3 was assessed using competitive reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: In the absence of CD8(+) T-cell depletion, the mean percent intimal occlusion was 28% (with 50% of vessels showing no intimal occlusion). This figure was reduced significantly to 12% and 80% of vessels showing no intimal occlusion in mice receiving anti-CD8 antibody. Depletion of CD8(+) T cells was associated with significantly reduced intragraft IFN-gamma, TGF-beta1 and CCR3 expression, whereas mRNA production of IL-4 and eotaxin was increased. CONCLUSION: Vascular intimal occlusion progresses in the complete absence of CD40-CD154 interactions, albeit to quite a small degree. The residual disease is significantly reduced by anti CD8(+) T-cell treatment, confirming the importance of CD40-CD154-independent CD8(+) T cells in the genesis of this disease.
